Hydrophilic antibody-drug conjugates

Patent metadata

Field	Value
Publication number	US-10933112-B2
Application number	US-201515118031-A
Country	US
Kind code	B2
Filing date	Feb 17, 2015
Priority date	Feb 17, 2014
Publication date	Mar 2, 2021
Grant date	Mar 2, 2021

Abstract

Hydrophilic Linkers, Drug-Linker compounds, Drug-Ligand Conjugate compounds and Ligand-Linkers and methods of making and using the same are provided.

First claim

What is claimed is:

1. A hydrophilic Drug-Ligand Conjugate Compound having the formula:

or a pharmaceutically acceptable salt or solvate thereof,
wherein:
L is a Ligand unit that specifically binds to a target;
L A is a Ligand attachment component;
L H is an optionally branched hydrophilic linker, each branch of L H having the formula:
- AA 1 -R L1 —R L2 —R L3

wherein:
AA 1 is a hydrophilic amino acid that forms a cleavable bond with the D E to which it is attached;
R L1 is optional and is a hydrophilic amino acid or an optionally substituted alkylene, which may share an atom with L A when R L1 is present and R L2 and R L3 are absent;
R L2 is optional and is selected from a hydrophilic amino acid and an optionally substituted alkylene, which may share an atom with L A when R L2 is present and R L3 is absent; and
R L3 is optional and is selected from a hydrophilic amino acid and an optionally substituted alkylene, which may share an atom with L A when R L3 is present;
the subscript p is an integer of from about 4 to about 20;
the subscript p′ is an integer of from 1 to 4;
and
each D E is an auristatin having the formula:

or a pharmaceutically acceptable salt or solvate thereof,
wherein:
R 1 and R 2 each are independently selected from the group consisting of hydrogen (H) and optionally substituted —C 1 -C 8 alkyl; with the proviso that both R 1 and R 2 are not H, unless both of R 3 and R 3′ are not H;
R 3 is selected from the group consisting of H and optionally substituted —C 1 -C 8 alkyl;
R 3′ is selected from the group consisting of H and optionally substituted —C 1 -C 8 alkyl, and at least one of R 3 and R 3′ is not H;
R 4 is selected from the group consisting of H and optionally substituted —C 1 -C 8 alkyl;
R 5 is selected from the group consisting of H and optionally substituted —C 1 -C 8 alkyl;
or R 4 and R 5 jointly form a carbocyclic ring and have the formula —(CR a R b ) n —, wherein R a and R b are independently selected from the group consisting of H and optionally substituted —C 1 -C 8 alkyl and n is selected from the group consisting of 2, 3, 4, 5 and 6;
R 6 is selected from the group consisting of H and optionally substituted —C 1 -C 8 alkyl;
R 7 is selected from the group consisting of H and optionally substituted —C 1 -C 8 alkyl;
each R 8 is independently selected from the group consisting of H, —OH, optionally substituted —C 1 -C 8 alkyl, and optionally substituted —O—(C 1 -C 8 alkyl);
R 12 is selected from the side chains of the group consisting of threonine, serine, asparagine, aspartic acid, glutamine, glutamic acid, homoserine, hydroxyvaline, furyl alanine, threonine(PO 3 H 2 ), pyrazolyl alanine, triazolyl alanine and thiazolyl alanine; or a pharmaceutically acceptable salt or solvate thereof;
wherein the left and right lines of L H indicate covalent attachments to the D E unit and L A , respectively; and
wherein the Compound has a hydrophilicity index of less than two.

2. The Compound of claim 1 , wherein L H comprises a modified peptide, wherein at least one R L1 , R L2 and R L3 is an amino acid that is covalently linked by a reactive group on its side chain to an adjacent group; or a pharmaceutically acceptable salt or solvate thereof.

3. The Compound of claim 1 , wherein R 12 is the side chain of L-threonine; or a pharmaceutically acceptable salt or solvate thereof.

4. The Compound of claim 1 , wherein p of the Compound is at least 8; or a pharmaceutically acceptable salt or solvate thereof.

5. The Compound of claim 4 , wherein p of the Compound is at least 10; or a pharmaceutically acceptable salt or solvate thereof.

6. The Compound of claim 4 , wherein p of the Compound is at least 16; or a pharmaceutically acceptable salt or solvate thereof.

7. The Compound of claim 1 , wherein L A is a succinimide or a hydrolyzed succinimide; or a pharmaceutically acceptable salt or solvate thereof.

8. The Compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the p' of the Compound is 1, and wherein the -L A -L H of the Compound have the formula:

wherein
R 21 is selected from the group consisting of —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CH 2 CH 2 CO 2 H, and —CH 2 CH 2 CH 2 CH 2 CO 2 H; and
R 22 is selected from the group consisting of —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 OH; and the left and right wavy lines indicate attachment to the D E and the Ligand unit (L), respectively; and the sulfur atom is from the Ligand unit.

9. The Compound of claim 1 , wherein the Ligand unit (L) of the Drug-Ligand Conjugate is a protein, polypeptide or peptide.

10. The Compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the Ligand unit (L) of the Compound is an antibody.

11. The Compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein L A is succinamide or succinamido diaminopropionic acid, each of which may be hydrolyzed.

12. The Compound of claim 1 having a formula selected from the group consisting of:

and pharmaceutically acceptable salts and solvates thereof, wherein S is a sulfur atom from the Ligand unit.

13. A pharmaceutical composition comprising an effective amount of the Compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient.

14. The Compound of claim 1 , wherein the p' of the Compound is 1; or a pharmaceutically acceptable salt or solvate thereof.

15. The Compound of claim 14 , wherein L H comprises a modified peptide, wherein at least one R L1 , R L2 and R L3 is an amino acid that is covalently linked by a reactive group on its side chain to an adjacent group; or a pharmaceutically acceptable salt or solvate thereof.

16. The Compound of claim 14 , wherein R 12 is the side chain of L-threonine; or a pharmaceutically acceptable salt or solvate thereof.

17. The Compound of claim 14 , wherein p of the Compound is at least 8; or a pharmaceutically acceptable salt or solvate thereof.

18. The Compound of claim 17 , wherein p of the Compound is at least 10; or a pharmaceutically acceptable salt or solvate thereof.

19. The Compound of claim 17 , wherein p of the Compound is at least 16; or a pharmaceutically acceptable salt or solvate thereof.

20. The Compound of claim 14 , wherein L A is a succinimide or a hydrolyzed succinimide; or a pharmaceutically acceptable salt or solvate thereof.

21. The Compound of claim 14 , wherein the Ligand unit (L) or the Drug-Ligand Conjugate is a protein, polypeptide or peptide.

22. The Compound of claim 14 , or a pharmaceutically acceptable salt or solvate thereof, wherein the Ligand unit (L) of the Compound is an antibody.

23. The Compound of claim 14 , or a pharmaceutically acceptabl

Assignees

• Seagen Inc

Inventors

• Doronina Svetlana
• Lyon Robert
• Senter Peter

Classifications

• A61K47/68031

  the drug being an auristatin · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61K47/6889 Primary

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title